RESUMO

There are contradictory reports on the role of the serine/threonine kinase isoform glycogen synthase kinase-3ß (GSK3ß) after injury to the central nervous system (CNS). Some report that GSK3 activity promotes axonal growth or myelin disinhibition, whilst others report that GSK3 activity prevents axon regeneration. In this study, we sought to clarify if suppression of GSK3ß alone and in combination with the cellular-stress-induced factor RTP801 (also known as REDD1: regulated in development and DNA damage response protein), using translationally relevant siRNAs, promotes retinal ganglion cell (RGC) survival and neurite outgrowth/axon regeneration. Adult mixed retinal cell cultures, prepared from rats at five days after optic nerve crush (ONC) to activate retinal glia, were treated with siRNA to GSK3ß (siGSK3ß) alone or in combination with siRTP801 and RGC survival and neurite outgrowth were quantified in the presence and absence of Rapamycin or inhibitory Nogo-A peptides. In in vivo experiments, either siGSK3ß alone or in combination with siRTP801 were intravitreally injected every eight days after ONC and RGC survival and axon regeneration was assessed at 24 days. Optimal doses of siGSK3ß alone promoted significant RGC survival, increasing the number of RGC with neurites without affecting neurite length, an effect that was sensitive to Rapamycin. In addition, knockdown of GSK3ß overcame Nogo-A-mediated neurite growth inhibition. Knockdown of GSK3ß after ONC in vivo enhanced RGC survival but not axon number or length, without potentiating glial activation. Knockdown of RTP801 increased both RGC survival and axon regeneration, whilst the combined knockdown of GSK3ß and RTP801 significantly increased RGC survival, neurite outgrowth, and axon regeneration over and above that observed for siGSK3ß or siRTP801 alone. These results suggest that GSK3ß suppression promotes RGC survival and axon initiation whilst, when in combination with RTP801, it also enhanced disinhibited axon elongation.

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Support from human genetics increases the probability of success in drug development. However, few examples exist of successful genomically-driven drug repositioning. Given that a Mendelian form of severe enterocolitis is due to up-regulation of the interleukin-18 (IL18) signaling pathway, and pharmacologic inhibition of IL18 has been shown to reverse this enterocolitis, we undertook a Mendelian randomization study to test the causal effect of elevated IL18 levels on inflammatory bowel disease susceptibility (IBD) in 12,882 cases and 21,770 controls. Mendelian randomization is an established method to assess the role of biomarkers in disease etiology in a manner that minimizes confounding and prevents reverse causation. Using three SNPs that explained almost 7% of the variance in IL18 level, we found that each genetically predicted standard deviation increase in IL18 was associated with an increase in IBD susceptibility (odds ratio = 1.22, 95% CI = 1.11-1.34, P-value = 6 × 10-5). This association was further validated in 25,042 IBD cases and 34,915 controls (odds ratio = 1.13, 95% CI = 1.05-1.20). Recently, an anti-IL18 monoclonal antibody, which decreased free IL18 levels, was found to be safe, yet ineffective in a phase II trial for type 2 diabetes. Taken together, these genomic findings implicated IBD as an alternative indication for anti-IL18 therapy, which should be tested in randomized controlled trials.

RESUMO

Waist-to-hip ratio (WHR) is a prominent cardiometabolic risk factor that increases cardio-metabolic disease risk independently of BMI and for which multiple genetic loci have been identified. However, WHR is a relatively crude proxy for fat distribution and it does not capture all variation in fat distribution. We here present a study of the role of coding genetic variants on fat mass in 6 distinct regions of the body, based on dual-energy X-ray absorptiometry imaging on more than 17k participants. We find that the missense variant CCDC92S70C, previously associated with WHR, is associated specifically increased leg fat mass and reduced visceral but not subcutaneous central fat. The minor allele-carrying transcript of CCDC92 is constitutively more highly expressed in adipose tissue samples. In addition, we identify two coding variants in SPATA20 and UQCC1 that are associated with arm fat mass. SPATA20K422R is a low-frequency variant with a large effect on arm fat only, and UQCC1R51Q is a common variant reaching significance for arm but showing similar trends in other subcutaneous fat depots. Our findings support the notion that different fat compartments are regulated by distinct genetic factors.

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Circulating levels of glycine have previously been associated with lower incidence of coronary heart disease (CHD) and type 2 diabetes (T2D) but it remains uncertain if glycine plays an aetiological role. We present a meta-analysis of genome-wide association studies for glycine in 80,003 participants and investigate the causality and potential mechanisms of the association between glycine and cardio-metabolic diseases using genetic approaches. We identify 27 genetic loci, of which 22 have not previously been reported for glycine. We show that glycine is genetically associated with lower CHD risk and find that this may be partly driven by blood pressure. Evidence for a genetic association of glycine with T2D is weaker, but we find a strong inverse genetic effect of hyperinsulinaemia on glycine. Our findings strengthen evidence for a protective effect of glycine on CHD and show that the glycine-T2D association may be driven by a glycine-lowering effect of insulin resistance.

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Osteoarthritis is the most common musculoskeletal disease and the leading cause of disability globally. Here, we performed a genome-wide association study for osteoarthritis (77,052 cases and 378,169 controls), analyzing four phenotypes: knee osteoarthritis, hip osteoarthritis, knee and/or hip osteoarthritis, and any osteoarthritis. We discovered 64 signals, 52 of them novel, more than doubling the number of established disease loci. Six signals fine-mapped to a single variant. We identified putative effector genes by integrating expression quantitative trait loci (eQTL) colocalization, fine-mapping, and human rare-disease, animal-model, and osteoarthritis tissue expression data. We found enrichment for genes underlying monogenic forms of bone development diseases, and for the collagen formation and extracellular matrix organization biological pathways. Ten of the likely effector genes, including TGFB1 (transforming growth factor beta 1), FGF18 (fibroblast growth factor 18), CTSK (cathepsin K), and IL11 (interleukin 11), have therapeutics approved or in clinical trials, with mechanisms of action supportive of evaluation for efficacy in osteoarthritis.

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Purpose: To determine if vitreous levels of the pro-fibrotic cytokine transforming growth factor beta2 (TGF-ß2) and its opposing regulator decorin predict subsequent proliferative vitreoretinopathy (PVR) development in patients with rhegmatogenous retinal detachment (RRD). Methods: We examined the effect of TGF-ß2 and decorin on epithelial-mesenchymal transition (EMT) and collagen expression in vitro using ARPE-19 cells, and we analyzed extracellular matrix marker expression in PVR membrane and internal limiting membrane patient samples. We performed a prospective noninterventional cohort study, recruiting 125 patients undergoing vitrectomy for RRD and macular hole surgery, measured vitreous levels of TGF-ß2 and decorin by ELISA, and followed them up for 6 months. Patients who did not develop PVR were compared to those who did, in order to determine whether vitreous TGF-ß2 and decorin levels predicted PVR development. Results: In vitro, TGF-ß2 induced EMT and collagen production. Decorin strongly inhibited EMT and collagen production at high levels. PVR membranes expressed high levels of fibrosis-associated proteins, consistent with EMT. Vitreous TGF-ß2 levels were unchanged between patients with macular holes and RRD who did or did not subsequently develop PVR. Average decorin levels were higher in the vitreous of RRD patients who subsequently developed PVR compared to those who did not, but at the measured vitreous concentrations (1-2 µg/mL), decorin did not demonstrate an in vitro inhibitory effect on EMT. Conclusions: In vitro, high concentrations of decorin inhibited EMT and fibrosis. At the levels seen in human vitreous, decorin did not prevent fibrosis or EMT in vitro, and higher initial vitreous decorin levels were associated with the development of postoperative PVR after vitrectomy to treat RRD, but did not reliably predict the outcome.

RESUMO

Importance: Pharmacological enhancers of lipoprotein lipase (LPL) are in preclinical or early clinical development for cardiovascular prevention. Studying whether these agents will reduce cardiovascular events or diabetes risk when added to existing lipid-lowering drugs would require large outcome trials. Human genetics studies can help prioritize or deprioritize these resource-demanding endeavors. Objective: To investigate the independent and combined associations of genetically determined differences in LPL-mediated lipolysis and low-density lipoprotein cholesterol (LDL-C) metabolism with risk of coronary disease and diabetes. Design, Setting, and Participants: In this genetic association study, individual-level genetic data from 392â¯220 participants from 2 population-based cohort studies and 1 case-cohort study conducted in Europe were included. Data were collected from January 1991 to July 2018, and data were analyzed from July 2014 to July 2018. Exposures: Six conditionally independent triglyceride-lowering alleles in LPL, the p.Glu40Lys variant in ANGPTL4, rare loss-of-function variants in ANGPTL3, and LDL-C-lowering polymorphisms at 58 independent genomic regions, including HMGCR, NPC1L1, and PCSK9. Main Outcomes and Measures: Odds ratio for coronary artery disease and type 2 diabetes. Results: Of the 392â¯220 participants included, 211â¯915 (54.0%) were female, and the mean (SD) age was 57 (8) years. Triglyceride-lowering alleles in LPL were associated with protection from coronary disease (approximately 40% lower odds per SD of genetically lower triglycerides) and type 2 diabetes (approximately 30% lower odds) in people above or below the median of the population distribution of LDL-C-lowering alleles at 58 independent genomic regions, HMGCR, NPC1L1, or PCSK9. Associations with lower risk were consistent in quintiles of the distribution of LDL-C-lowering alleles and 2 × 2 factorial genetic analyses. The 40Lys variant in ANGPTL4 was associated with protection from coronary disease and type 2 diabetes in groups with genetically higher or lower LDL-C. For a genetic difference of 0.23 SDs in LDL-C, ANGPTL3 loss-of-function variants, which also have beneficial associations with LPL lipolysis, were associated with greater protection against coronary disease than other LDL-C-lowering genetic mechanisms (ANGPTL3 loss-of-function variants: odds ratio, 0.66; 95% CI, 0.52-0.83; 58 LDL-C-lowering variants: odds ratio, 0.90; 95% CI, 0.89-0.91; P for heterogeneity = .009). Conclusions and Relevance: Triglyceride-lowering alleles in the LPL pathway are associated with lower risk of coronary disease and type 2 diabetes independently of LDL-C-lowering genetic mechanisms. These findings provide human genetics evidence to support the development of agents that enhance LPL-mediated lipolysis for further clinical benefit in addition to LDL-C-lowering therapy.

RESUMO

BACKGROUND & AIMS: Advancing liver disease results in deleterious changes in a number of critical organs. The ability to measure structure, blood flow and tissue perfusion within multiple organs in a single scan has implications for determining the balance of benefit vs. harm for therapies. Our aim was to establish the feasibility of magnetic resonance imaging (MRI) to assess changes in Compensated Cirrhosis (CC), and relate this to disease severity and future liver-related outcomes (LROs). METHODS: A total of 60 patients with CC, 40 healthy volunteers and 7 patients with decompensated cirrhosis were recruited. In a single scan session, MRI measures comprised phase-contrast MRI vessel blood flow, arterial spin labelling tissue perfusion, T1 longitudinal relaxation time, heart rate, cardiac index, and volume assessment of the liver, spleen and kidneys. We explored the association between MRI parameters and disease severity, analysing differences in baseline MRI parameters in the 11 (18%) patients with CC who experienced future LROs. RESULTS: In the liver, compositional changes were reflected by increased T1 in progressive disease (pâ¯<0.001) and an increase in liver volume in CC (pâ¯=â¯0.006), with associated progressive reduction in liver (pâ¯<0.001) and splenic (pâ¯<0.001) perfusion. A significant reduction in renal cortex T1 and increase in cardiac index and superior mesenteric arterial blood flow was seen with increasing disease severity. Baseline liver T1 (pâ¯=â¯0.01), liver perfusion (pâ¯<0.01), and renal cortex T1 (pâ¯<0.01) were significantly different in patients with CC who subsequently developed negative LROs. CONCLUSIONS: MRI enables the contemporaneous assessment of organs in liver cirrhosis in a single scan without the requirement for a contrast agent. MRI parameters of liver T1, renal T1, hepatic and splenic perfusion, and superior mesenteric arterial blood flow were related to the risk of LROs. LAY SUMMARY: This study assesses the changes to structure, blood flow and perfusion that occur in the key organs (liver, spleen and kidney) associated with severe liver disease (Compensated Cirrhosis), using magnetic resonance imaging. The magnetic resonance imaging measures which changed with disease severity and were related to negative liver-related clinical outcomes are described.

RESUMO

In the originally published version of this Article, the affiliation details for Santi González, Jian'an Luan and Claudia Langenberg were inadvertently omitted. Santi González should have been affiliated with 'Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034 Barcelona, Spain', and Jian'an Luan and Claudia Langenberg should have been affiliated with 'MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK'. Furthermore, the abstract contained an error in the SNP ID for the rare variant in chromosome Xq23, which was incorrectly given as rs146662057 and should have been rs146662075. These errors have now been corrected in both the PDF and HTML versions of the Article.

RESUMO

Glaucoma is the leading cause of irreversible blindness globally 1 . Despite its gravity, the disease is frequently undiagnosed in the community 2 . Raised intraocular pressure (IOP) is the most important risk factor for primary open-angle glaucoma (POAG)3,4. Here we present a meta-analysis of 139,555 European participants, which identified 112 genomic loci associated with IOP, 68 of which are novel. These loci suggest a strong role for angiopoietin-receptor tyrosine kinase signaling, lipid metabolism, mitochondrial function and developmental processes underlying risk for elevated IOP. In addition, 48 of these loci were nominally associated with glaucoma in an independent cohort, 14 of which were significant at a Bonferroni-corrected threshold. Regression-based glaucoma-prediction models had an area under the receiver operating characteristic curve (AUROC) of 0.76 in US NEIGHBORHOOD study participants and 0.74 in independent glaucoma cases from the UK Biobank. Genetic-prediction models for POAG offer an opportunity to target screening and timely therapy to individuals most at risk.

RESUMO

AIMS/HYPOTHESIS: Gene-macronutrient interactions may contribute to the development of type 2 diabetes but research evidence to date is inconclusive. We aimed to increase our understanding of the aetiology of type 2 diabetes by investigating potential interactions between genes and macronutrient intake and their association with the incidence of type 2 diabetes. METHODS: We investigated the influence of interactions between genetic risk scores (GRSs) for type 2 diabetes, insulin resistance and BMI and macronutrient intake on the development of type 2 diabetes in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a prospective case-cohort study across eight European countries (N = 21,900 with 9742 incident type 2 diabetes cases). Macronutrient intake was estimated from diets reported in questionnaires, including proportion of energy derived from total carbohydrate, protein, fat, plant and animal protein, saturated, monounsaturated and polyunsaturated fat and dietary fibre. Using multivariable-adjusted Cox regression, we estimated country-specific interaction results on the multiplicative scale, using random-effects meta-analysis. Secondary analysis used isocaloric macronutrient substitution. RESULTS: No interactions were identified between any of the three GRSs and any macronutrient intake, with low-to-moderate heterogeneity between countries (I2 range 0-51.6%). Results were similar using isocaloric macronutrient substitution analyses and when weighted and unweighted GRSs and individual SNPs were examined. CONCLUSIONS/INTERPRETATION: Genetic susceptibility to type 2 diabetes, insulin resistance and BMI did not modify the association between macronutrient intake and incident type 2 diabetes. This suggests that macronutrient intake recommendations to prevent type 2 diabetes do not need to account for differences in genetic predisposition to these three metabolic conditions.

RESUMO

Detailed phenotyping is required to deepen our understanding of the biological mechanisms behind genetic associations. In addition, the impact of potentially modifiable risk factors on disease requires analytical frameworks that allow causal inference. Here, we discuss the characteristics of Recall-by-Genotype (RbG) as a study design aimed at addressing both these needs. We describe two broad scenarios for the application of RbG: studies using single variants and those using multiple variants. We consider the efficacy and practicality of the RbG approach, provide a catalogue of UK-based resources for such studies and present an online RbG study planner.

RESUMO

The reanalysis of existing GWAS data represents a powerful and cost-effective opportunity to gain insights into the genetics of complex diseases. By reanalyzing publicly available type 2 diabetes (T2D) genome-wide association studies (GWAS) data for 70,127 subjects, we identify seven novel associated regions, five driven by common variants (LYPLAL1, NEUROG3, CAMKK2, ABO, and GIP genes), one by a low-frequency (EHMT2), and one driven by a rare variant in chromosome Xq23, rs146662057, associated with a twofold increased risk for T2D in males. rs146662057 is located within an active enhancer associated with the expression of Angiotensin II Receptor type 2 gene (AGTR2), a modulator of insulin sensitivity, and exhibits allelic specific activity in muscle cells. Beyond providing insights into the genetics and pathophysiology of T2D, these results also underscore the value of reanalyzing publicly available data using novel genetic resources and analytical approaches.

RESUMO

To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (>80% of low-frequency coding variants in ~82 K Europeans via the exome chip, and ~90% of low-frequency non-coding variants in ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.

RESUMO

This case report describes a 9-year-old male who presented to the emergency department with 2 days' history of left painful red eye. On initial examination, his outside medical records indicated that he had bilateral subluxated lenses and had undergone left eye lensectomy with glued intrascleral fixation of an intraocular lens 8 weeks earlier. Vision in left eye was poor from first postoperative day but with no undue pain or redness, and poor vision was attributed to possible vitreous bleed. Subsequent postoperative course was uneventful. He was discharged from ophthalmic care on topical steroids and antibiotic drops, one week postsurgery. The eye was healing well until he developed pain, for which ophthalmic care was sought. He underwent anterior chamber tap with intravitreal injections. Aqueous samples were positive for Staphylococcus aureus DNA by polymerase chain reaction. Post vitrectomy and implant removal, his recovery was good and vision improved to 0.50 LogMar with aphakic correction.

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